RESUMO
BACKGROUND: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. METHODS: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. RESULTS: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18-75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. CONCLUSIONS: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD.
Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Proteínas de Neurofilamentos , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/sangue , Proteínas de Neurofilamentos/sangue , Proteínas de Neurofilamentos/genética , Feminino , Masculino , Pessoa de Meia-Idade , Apolipoproteína E4/genética , Idoso , Estudos Transversais , Apolipoproteína E2/genética , Apolipoproteína E2/sangue , Presenilina-1/genética , Adulto , Cognição/fisiologia , Biomarcadores/sangue , Testes Neuropsicológicos , Mutação , Heterozigoto , GenótipoRESUMO
Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aß), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aß), the goal of this work was to examine Aß-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aß-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mutação , Presenilina-1 , Animais , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Quimiotaxia/genética , Modelos Animais de Doenças , Presenilina-1/genética , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologiaRESUMO
BACKGROUND: Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-ß (Aß) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aß-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aß concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease. METHODS: 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aß1-38, Aß1-40 and Aß1-42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models. RESULTS: Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aß peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aß1-38 compared to controls (p < 0.05). There was no difference in Aß1-42/1-40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aß1-42/1-40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC. CONCLUSION: These data show very strong mutation-specific effects on Aß profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aß ratio might be a poor indicator of brain Aß pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Presenilina-1 , Presenilina-2 , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Masculino , Feminino , Suécia , Pessoa de Meia-Idade , Presenilina-1/genética , Presenilina-2/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/sangue , Idoso , Mutação , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Estudos Longitudinais , Estudos de Coortes , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/genéticaRESUMO
BACKGROUND: Microglial cell iron load and inflammatory activation are significant hallmarks of late-stage Alzheimer's disease (AD). In vitro, microglia preferentially upregulate the iron importer, divalent metal transporter 1 (DMT1, gene name Slc11a2) in response to inflammatory stimuli, and excess iron can augment cellular inflammation, suggesting a feed-forward loop between iron import mechanisms and inflammatory signaling. However, it is not understood whether microglial iron import mechanisms directly contribute to inflammatory signaling and chronic disease in vivo. These studies determined the effects of microglial-specific knockdown of Slc11a2 on AD-related cognitive decline and microglial transcriptional phenotype. METHODS: In vitro experiments and RT-qPCR were used to assess a role for DMT1 in amyloid-ß-associated inflammation. To determine the effects of microglial Slc11a2 knockdown on AD-related phenotypes in vivo, triple-transgenic Cx3cr1Cre-ERT2;Slc11a2flfl;APP/PS1+or - mice were generated and administered corn oil or tamoxifen to induce knockdown at 5-6 months of age. Both sexes underwent behavioral analyses to assess cognition and memory (12-15 months of age). Hippocampal CD11b+ microglia were magnetically isolated from female mice (15-17 months) and bulk RNA-sequencing analysis was conducted. RESULTS: DMT1 inhibition in vitro robustly decreased Aß-induced inflammatory gene expression and cellular iron levels in conditions of excess iron. In vivo, Slc11a2KD APP/PS1 female, but not male, mice displayed a significant worsening of memory function in Morris water maze and a fear conditioning assay, along with significant hyperactivity compared to control WT and APP/PS1 mice. Hippocampal microglia from Slc11a2KD APP/PS1 females displayed significant increases in Enpp2, Ttr, and the iron-export gene, Slc40a1, compared to control APP/PS1 cells. Slc11a2KD cells from APP/PS1 females also exhibited decreased expression of markers associated with subsets of disease-associated microglia (DAMs), such as Apoe, Ctsb, Ly9, Csf1, and Hif1α. CONCLUSIONS: This work suggests a sex-specific role for microglial iron import gene Slc11a2 in propagating behavioral and cognitive phenotypes in the APP/PS1 model of AD. These data also highlight an association between loss of a DAM-like phenotype in microglia and cognitive deficits in Slc11a2KD APP/PS1 female mice. Overall, this work illuminates an iron-related pathway in microglia that may serve a protective role during disease and offers insight into mechanisms behind disease-related sex differences.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Proteínas de Transporte de Cátions , Camundongos Transgênicos , Microglia , Presenilina-1 , Caracteres Sexuais , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Microglia/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Camundongos , Feminino , Masculino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Cognição/fisiologia , Camundongos Endogâmicos C57BL , Ferro/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that can result in neurotoxicity and an imbalance in gut microbiota. Probiotics have been shown to play an important role in regulating the gut microbiota, but their viability and bioactivity are often compromised as they traverse the gastrointestinal tract, thereby reducing their efficacy and limiting their clinical utility. RESULTS: In this work, layer-by-layer (LbL) encapsulation technology was used to encapsulate Lactiplantibacillus plantarum (LP) to improve the above shortcomings. Studies in APPswe/PS1dE9 (APP/PS1) transgenic mice show that LbL-encapsulated LP ((CS/SP)2-LP) protects LP from gastrointestinal damage while (CS/SP)2-LP treatment It improves brain neuroinflammation and neuronal damage in AD mice, reduces Aß deposition, improves tau protein phosphorylation levels, and restores intestinal barrier damage in AD mice. In addition, post-synaptic density protein 95 (PSD-95) expression increased in AD mice after treatment, indicating enhanced synaptic plasticity. Fecal metabolomic and microbiological analyzes showed that the disordered intestinal microbiota composition of AD mice was restored and short-chain fatty acids (SCFAs) levels were significantly increased after (CS/SP)2-LP treatment. CONCLUSION: Overall, the above evidence suggests that (CS/SP)2-LP can improve AD symptoms by restoring the balance of intestinal microbiota, and (CS/SP)2-LP treatment will provide a new method to improve the symptoms of AD patients.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Microbioma Gastrointestinal , Camundongos Transgênicos , Probióticos , Animais , Camundongos , Probióticos/farmacologia , Masculino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Proteínas tau/metabolismo , Presenilina-1/genética , Peptídeos beta-Amiloides/metabolismo , Lactobacillus plantarumAssuntos
Doença de Alzheimer , Calcinose , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Calcinose/genética , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Presenilina-1/genéticaRESUMO
Familial Alzheimer's disease (FAD) is a chronic neurological condition that progresses over time. Currently, lacking a viable treatment, the use of multitarget medication combinations has generated interest as a potential FAD therapy approach. In this study, we examined the effects of 4-phenylbutyric acid (4-PBA) and methylene blue (MB) either separately or in combination on PSEN1 I416T cholinergic-like neuron cells (ChLNs), which serve as a model for FAD. We found that MB was significantly efficient at reducing the accumulation of intracellular Aß, phosphorylation of TAU Ser202/Thr205, and increasing Δψm, whereas 4-PBA was significantly efficient at diminishing oxidation of DJ-1Cys106-SH, expression of TP53, and increasing ACh-induced Ca2+ influx. Both agents were equally effective at blunting phosphorylated c-JUN at Ser63/Ser73 and activating caspase 3 (CASP3) into cleaved caspase 3 (CC3) on mutant cells. Combination of MB and 4-PBA at middle (0.1, 1) concentration significantly reduced iAß, p-TAU, and oxDJ-1 and augmented the ACh-induced Ca2+ influx compared to combined agents at low (0.05, 0.5) or high (0.5, 5) concentration. However, combined MB and 4-PBA were efficient only at dropping DJ-1Cys106-SO3 and increasing ACh-induced Ca2+ inward in mutant ChLNs. Our data show that the reagents MB and 4-PBA alone possess more than one action (e.g., antiamyloid, antioxidant, anti-TAU, antiapoptotic, and ACh-induced Ca2+ influx enhancers), that in combination might cancel or diminish each other. Together, these results strongly argue that MB and 4-PBA might protect PSEN1 I416T ChLNs from Aß-induced toxicity by working intracellularly as anti-Aß and anti-Tau agents, improving Δψm and cell survival, and extracellularly, by increasing ACh-induced Ca2+ ion influx. MB and 4-PBA are promising drugs with potential for repurposing in familial AD.
Assuntos
Doença de Alzheimer , Antioxidantes , Apoptose , Azul de Metileno , Fenilbutiratos , Presenilina-1 , Presenilina-1/genética , Presenilina-1/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Azul de Metileno/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Fenilbutiratos/farmacologia , Proteínas tau/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cálcio/metabolismo , Animais , Fosforilação/efeitos dos fármacosRESUMO
Alzheimer's disease (AD), characterized by cognitive decline, is increasingly recognized as a disorder marked by synaptic loss and dysfunction. Despite this understanding, the underlying pathophysiological mechanisms contributing to synaptic impairment remain largely unknown. In this study, we elucidate a previously undiscovered signaling pathway wherein the S-nitrosylation of the Cdk5 activator p39, a post-translational modification involving the addition of nitric oxide to protein cysteine residues, plays a crucial role in synaptic dysfunction associated with AD. Our investigation reveals heightened p39 S-nitrosylation in the brain of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. Additionally, soluble amyloid-ß oligomers (Aß), implicated in synaptic loss in AD, induce p39 S-nitrosylation in cultured neurons. Notably, we uncover that p39 protein level is regulated by S-nitrosylation, with nitric oxide S-nitrosylating p39 at Cys265 and subsequently promoting its degradation. Furthermore, our study demonstrates that S-nitrosylation of p39 at Cys265 significantly contributes to amyloid-ß (Aß) peptide-induced dendrite retraction and spine loss. Collectively, our findings highlight S-nitrosylation of p39 as a novel aberrant redox protein modification involved in the pathogenesis of AD, suggesting its potential as a therapeutic target for the disease.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos Transgênicos , Animais , Peptídeos beta-Amiloides/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sinapses/metabolismo , Óxido Nítrico/metabolismo , Processamento de Proteína Pós-Traducional , Proteólise , Neurônios/metabolismo , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Humanos , Presenilina-1/metabolismo , Presenilina-1/genética , Camundongos Endogâmicos C57BL , FosfotransferasesRESUMO
Objective: The objective of the study is to investigate whether quercetin ameliorates Alzheimer's disease (AD)-like pathology in APP/PS1 double transgenic mice and its hypothesized mechanism, contributing to the comprehension of AD pathogenesis. Methods: A total of 30 APP/PS1 transgenic mice were randomized into model group (APP/PS1), quercetin group (APP/PS1+Q), and donepezil hydrochloride group (APP/PS1+DON). Simultaneously, there were 10 C57 mice of the same age served as a control group. Three months posttreatment, the effects of quercetin on AD mice were evaluated using the Morris water maze (MWM) test, Y maze experiment, immunohistochemistry, immunofluorescence, and western blotting. Results: Results from the water maze and Y maze indicated that quercetin significantly improved cognitive impairment in APP/PS1 transgenic AD mice. Additionally, serum enzyme-linked immunosorbent assay (ELISA) results demonstrated that quercetin elevated MDA, superoxide dismutase (SOD), CAT, GSH, acetylcholine (ACh), and acetylcholinesterase (AChE) levels in AD mice. Hematoxylin-eosin (HE) staining, Nissl staining, and hippocampal tissue thioflavine staining revealed that quercetin reduced neuronal damage and Aß protein accumulation in AD mice. Western blot validated protein expression in the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway associated with oxidative stress and apoptosis, confirming quercetin's potential molecular mechanism of enhancing AD mouse cognition. Furthermore, western blot findings indicate that quercetin significantly alters protein expression in the Keap1/Nrf2/HO-1 pathway. Moreover, molecular docking analysis suggests that Keap1, NQO1, HO-1, caspase-3, Bcl-2, and Bax proteins in the Keap1/Nrf2/HO-1 pathway may be potential regulatory targets of quercetin. These findings will provide a molecular basis for quercetin's clinical application in AD treatment. Conclusion: Quercetin can improve cognitive impairment and AD-like pathology in APP/PS1 double transgenic mice, potentially related to quercetin's activation of the Keap1/Nrf2/HO-1 pathway and reduction of cell apoptosis.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Apoptose , Encéfalo , Disfunção Cognitiva , Modelos Animais de Doenças , Heme Oxigenase-1 , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Quercetina , Animais , Quercetina/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Heme Oxigenase-1/metabolismo , Apoptose/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Transdução de Sinais/efeitos dos fármacos , Presenilina-1/genética , Presenilina-1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Antioxidantes/farmacologia , Antioxidantes/metabolismoRESUMO
Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Animais Recém-Nascidos , Neurônios Colinérgicos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neocórtex , Animais , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos , Neocórtex/metabolismo , Neocórtex/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Neurônios Colinérgicos/patologia , Neurônios Colinérgicos/metabolismo , Presenilina-1/genética , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/genética , Lesões Encefálicas/patologia , Lesões Encefálicas/metabolismo , Lesões Encefálicas/genética , Colina O-Acetiltransferase/metabolismo , Colina O-Acetiltransferase/genética , Humanos , Masculino , Modelos Animais de DoençasRESUMO
Background: Presenilin 1 (PSEN1) is one of the genes linked to the prevalence of early onset Alzheimer's disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1, including those with a deleted exon 9 (Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1ΔE9/+ pigs to study their relevance to clinical Alzheimer's diseases. Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer's disease.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Presenilina-1 , Animais , Presenilina-1/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Suínos , Mutação/genética , Encéfalo/patologia , Encéfalo/metabolismo , Animais Geneticamente Modificados , Desenvolvimento Ósseo/genética , Coluna Vertebral/patologia , Coluna Vertebral/anormalidadesRESUMO
Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer's disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30âs, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.
Assuntos
Doença de Alzheimer , Mutação , Testes Neuropsicológicos , Presenilina-1 , Humanos , Presenilina-1/genética , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Colômbia , Mutação/genética , Disfunção Cognitiva/genética , Cognição/fisiologiaRESUMO
Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-ß (Aß) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aß peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aß and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aß filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aß filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aß filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Placa Amiloide , Presenilina-1 , Proteínas tau , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Humanos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Peptídeos beta-Amiloides/metabolismo , Presenilina-1/genética , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Mutação , Feminino , MasculinoRESUMO
Alzheimer's disease (AD) is a neurodegenerative process responsible for almost 70% of all cases of dementia. The clinical signs consist in progressive and irreversible loss of memory, cognitive, and behavioral functions. The main histopathological hallmark is the accumulation of amyloid-ß (Aß) peptide fibrils in the brain. To date, the origin of Aß has not been determined. Recent studies have shown that the gut microbiota produces Aß, and dysbiotic states have been identified in AD patients and animal models of AD. Starting from the hypothesis that maintaining or restoring the microbiota's eubiosis is essential to control Aß's production and deposition in the brain, we used a mixture of probiotics and prebiotics (symbiotic) to treat APPPS1 male and female mice, an animal model of AD, from 2 to 8 months of age and evaluated their cognitive performances, mucus secretion, Aß serum concentration, and microbiota composition. The results showed that the treatment was able to prevent the memory deficits, the reduced mucus secretion, the increased Aß blood levels, and the imbalance in the gut microbiota found in APPPS1 mice. The present study demonstrates that the gut-brain axis plays a critical role in the genesis of cognitive impairment, and that modulation of the gut microbiota can ameliorate AD's symptomatology.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Disfunção Cognitiva , Modelos Animais de Doenças , Microbioma Gastrointestinal , Camundongos Transgênicos , Prebióticos , Probióticos , Animais , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/terapia , Doença de Alzheimer/terapia , Feminino , Camundongos , Masculino , Presenilina-1/genética , Eixo Encéfalo-Intestino , Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , CogniçãoRESUMO
Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-ß pathology.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Doença de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Modelos Animais de Doenças , Camundongos Transgênicos , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Humanos , Camundongos , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMO
OBJECTIVE: Studies have shown that electroacupuncture (EA) can alleviate cognitive impairments from Alzheimer's disease (AD) by regulating the expression of adenosine monophosphate-activated protein kinase (AMPK), but the specific mechanism involved remains to be elucidated. Therefore, this study explores the potential mechanism by which EA improves cognitive function from the perspective of mitochondrial dynamics. METHODS: The four-month-old transgenic mice with amyloid precursor protein (APP)/presenilin 1 (PS1) and AMPKα1-subunit conditional knockout (AMPKα1-cKO) were used for experiments. To evaluate the effects of EA treatment on cognitive function, the T-maze and Morris water maze were used. In addition, chemical exchange saturation transfer, thioflavin staining, transmission electron microscopy, mitochondrial membrane potential, and Western blotting were used to examine the potential mechanisms underlying the effects of EA on APP/PS1 mice. RESULTS: Both APP/PS1 mice and AMPKα1-cKO mice exhibited dysfunction in mitochondrial dynamics accompanied by learning and memory impairment. Inactivation of the AMPK/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) pathway increased pathological amyloid-ß (Aß) deposition and aggravated the dysfunction in mitochondrial dynamics. In addition, EA rescued learning and memory deficits in APP/PS1 mice by activating the AMPK/PGC-1α pathway, specifically by reducing pathological Aß deposition, normalizing energy metabolism, protecting the structure and function of mitochondria, increasing the levels of mitochondrial fusion proteins, and downregulating the expression of fission proteins. However, the therapeutic effect of EA on cognition in APP/PS1 mice was hindered by AMPKα1 knockout. CONCLUSION: The regulation of hippocampal mitochondrial dynamics and reduction in Aß deposition via the AMPK/PGC-1α pathway are critical for the ability of EA to ameliorate cognitive impairment in APP/PS1 mice. Please cite this article as: Jia WW, Lin HW, Yang MG, Dai YL, Ding YY, Xu WS, Wang SN, Cao YJ, Liang SX, Wang ZF, Chen C, Liu WL. Electroacupuncture activates AMPKα1 to improve learning and memory in the APP/PS1 mouse model of early Alzheimer's disease by regulating hippocampal mitochondrial dynamics. J Integr Med. 2024; 22(5): 588-599.
Assuntos
Proteínas Quinases Ativadas por AMP , Doença de Alzheimer , Modelos Animais de Doenças , Eletroacupuntura , Hipocampo , Dinâmica Mitocondrial , Animais , Masculino , Camundongos , Doença de Alzheimer/terapia , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Doença de Alzheimer/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/metabolismo , Aprendizagem , Aprendizagem em Labirinto , Memória , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Presenilina-1/genéticaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated. METHODS: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases. RESULTS: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase. CONCLUSIONS: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Encéfalo , Modelos Animais de Doenças , Ciclo Estral , Lipidômica , Lipídeos , Camundongos Transgênicos , Animais , Feminino , Ciclo Estral/fisiologia , Ciclo Estral/sangue , Lipidômica/métodos , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/sangue , Precursor de Proteína beta-Amiloide/genética , Lipídeos/sangue , Presenilina-1/genética , Camundongos , Metabolismo dos Lipídeos/fisiologia , Camundongos Endogâmicos C57BLRESUMO
Nonhuman primates (NHPs), which are closely related to humans, are useful in biomedical research, and an increasing number of NHP disease models have been reported using gene editing. However, many disease-related genes cause perinatal death when manipulated homozygously by gene editing. In addition, NHP resources, which are limited, should be efficiently used. Here, to address these issues, we developed a method of introducing heterozygous genetic modifications into common marmosets by combining Platinum transcription activator-like effector nuclease (TALEN) and a gene-editing strategy in oocytes. We succeeded in introducing the heterozygous exon 9 deletion mutation in the presenilin 1 gene, which causes familial Alzheimer's disease in humans, using this technology. As a result, we obtained animals with the expected genotypes and confirmed several Alzheimer's disease-related biochemical changes. This study suggests that highly efficient heterozygosity-oriented gene editing is possible using TALEN and oocytes and is an effective method for producing genetically modified animals.
Assuntos
Callithrix , Éxons , Edição de Genes , Heterozigoto , Presenilina-1 , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição , Animais , Callithrix/genética , Edição de Genes/métodos , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Presenilina-1/genética , Feminino , Modelos Animais de Doenças , Doença de Alzheimer/genética , Animais Geneticamente Modificados/genética , Oócitos/metabolismoRESUMO
Objective To explore the mechanism of fasudil improving cognitive dysfunction in amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice based on mitophagy and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway. Methods APP/PS1 mice were divided into model group and treatment group, and C57BL/6 mice were used as control group. The treatment group was given intraperitoneal injection of Fasudil (25 mg/kg) once daily for 2 months, while the control group and the model group were injected with the same volume of normal saline. The behavior of mice was detected by water maze and Y maze test; Nissl staining and neuron-specific nuclear antigen (NeuN) immunofluorescence histochemical staining were used to evaluate the number and morphology of neurons. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining was used to detect neuronal apoptosis; The expression of P62 and NLRP3 was detected by immunofluorescence histochemical staining; Real time fluorescence quantitative PCR was used to detect the mRNA expression levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) -induced putative kinase 1 (PINK1), Parkin and NLRP3; Western blot analysis was used to detect the expression of PINK1, Parkin, P62, microtubule-associated protein 1 light chain 3 (LC3), NLRP3, adapter protein apoptosis-associated speck-like protein (ASC) and interleukin-18 (IL-18). Results The results of the water maze and Y maze showed that the cognitive behavior of mice in treatment group was significantly improved, and their spatial memory and exploration abilities were significantly enhanced; The results of Nissl staining and NeuN immunofluorescence histochemical staining showed that the number of neurons and Nissl bodies were lower in the model group than that in the control group, while the morphology and number of neurons were improved after fasudil treatment. The results of TUNEL staining also showed that the number of apoptotic cells in the brain tissue of APP/PS1 mice were decreased after fasudil treatment; Compared with the control group, the expression of PINK1 and Parkin in the model group decreased, while the expression of P62, LC3, NLRP3, ASC and IL-18 increased. After treatment with fasudil, the expression of PINK1, Parkin, and LC3 increased, while the expression of P62, NLRP3, ASC, and IL-18 decreased. Conclusions Fasudil can improve the cognitive function and neuronal damage in APP/PS1 mice, and its mechanism may be related to promoting mitochondrial autophagy and inhibiting the activation of NLRP3 inflammasomes.
Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina , Cognição , Inflamassomos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitofagia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Mitofagia/efeitos dos fármacos , Camundongos , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Cognição/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Masculino , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas QuinasesRESUMO
Alzheimer's disease (AD) is closely associated with the neurotoxic effects of amyloid-ß (Aß), leading to synaptic damage, neuronal loss and cognitive dysfunction. Previous in vitro studies have demonstrated the potential of corilagin to counteract Aß-induced oxidative stress, inflammatory injury, and ß-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity in Aß production. However, the in vivo protective effects of corilagin on Alzheimer's disease remain unexplored. The purpose of this study was to investigate the protective effects of corilagin on APP/PS1 mice and the underlying mechanisms. The cognitive function of the mice was assessed by step-through passive avoidance and Morris water maze tests. Nissl staining was used to evaluate neuronal damage in the hippocampus. ELISA and Western blotting analyses were used to determine the associated protein expression. Transmission electron microscopy was utilized to observe the synaptic ultrastructure of hippocampal neurons. Golgi staining was applied to assess dendritic morphology and dendritic spine density in hippocampal pyramidal neurons. Immunohistochemistry and Western blotting were performed to examine the expression of synaptic-associated proteins. The results showed that corilagin improves learning and memory in APP/PS1 mice, reduces hippocampal neuron damage, inhibits BACE1 and reduces Aß generation. It also improves synaptic plasticity and the expression of synaptic-associated proteins. Corilagin effectively reduces Aß generation by inhibiting BACE1, ultimately reducing neuronal loss and enhancing synaptic plasticity to improve synaptic transmission. This study sheds light on the potential therapeutic role of corilagin in Alzheimer's disease.